DESCRIPTION: (Applicant's Abstract) Macrophages are important mediators of anticancer responses. However, many tumor types produce molecules that convert macrophages into suppressor cells. Because many conventional cancer treatments target only tumor cells, the clinical success or failure of chemotherapies may be determined partly by the activation status of the host's macrophages. The anticancer drug Taxol(TM) shows significant clinical success against several cancer types, and recent work indicates that Taxol provides potent activation signals to macrophages. Thus, Taxol's clinical success may be attributable to its ability to activate macrophages and reverse tumor-induced macrophage dysfunction. This project will determine the significance of Taxol-activated macrophages during tumor rejection. The specific aims of this research are to: 1) identify whether Taxol stimulates macrophage expression of surface molecules associated with lymphocyte activation and tumor rejection; 2) elucidate whether Taxol activates macrophages to produce cytokines necessary for antitumor responses; 3) show whether macrophage activation by Taxol is required for tumor growth delay or rejection; and 4) determine whether Taxol reverses tumor-induced immunosuppression. The first specific aim will use flow cytometry to determine whether Taxol increases expression of major histocompatibility complex class II molecules and B7 antigens, which are required for the activation of tumor-specific T cells. The second specific aim will use specific bioassays to measure Taxol-activated macrophage production of interleukin-12 and interleukin-15. These two cytokines enhance T cell and natural killer cell activation, proliferation, and cytotoxic activities during tumor rejection. The third specific aim will use two similar mouse strains that differ solely by the responsiveness of their macrophages to Taxol. Comparison of tumor growth delay or rejection mediated by in vivo Taxol administration should reveal whether Taxol-activated macrophages contribute significantly to tumor rejection processes. The fourth specific aim will evaluate cytotoxic activities in tumor-proximal macrophages and assess suppressor cell activities in tumor-distal macrophages from tumor-bearing hosts that receive systemic Taxol treatment. These experiments should show whether Taxol reverses tumor-induced macrophage dysfunction. Collectively, the studies outlined in this application should provide insight into the immunotherapeutic properties of Taxol on macrophages and suggest improved strategies for cancer treatment.